Lipid-dependent regulation of human Th17 cell function

人类 Th17 细胞功能的脂质依赖性调节

• 批准号: 9176733
• 负责人: Jun R. Huh
• 金额: $ 44.27万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9176733
• 关键词: Adverse effects; Arthritis; Autoimmune Diseases; Autoimmune Process; Biogenesis; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Chemicals; Colitis; Cytoplasm; Data; Development; Disease; Disease model; Effector Cell; Family; Fatty Acids; Fatty Liver; Gene Expression; Gene Targeting; Genes; Genetic Screening; Genetic screening method; Goals; Helper-Inducer T-Lymphocyte; Human; Immune; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-17; Kinetics; Lead; Ligands; Light; Link; Lipids; Liver diseases; Memory; Metabolic; Metabolism; Modeling; Molecular; Multiple Sclerosis; Mus; Nonesterified Fatty Acids; Nuclear Hormone Receptors; Organelles; Orphan; PPAR gamma; Pathology; Pathway interactions; Physiological; Play; Polyunsaturated Fatty Acids; Production; Proteins; Psoriasis; Regulation; Regulatory T-Lymphocyte; Retinoids; Role; Specificity; Sterols; T cell differentiation; T-Lymphocyte; Testing; Triglycerides; abstracting; chemical genetics; cytokine; gain of function; knock-down; lipid metabolism; macromolecule; novel; novel therapeutics; programs; receptor; response; small hairpin RNA; small molecule; treatment strategy

Abstract Th17 cells are an Interleukin-17-producing subset of CD4+ T effector cells that are centrally implicated in many human inflammatory and autoimmune diseases, from inflammatory bowel disease to multiple sclerosis. The retinoid orphan receptor gamma t (RORγt), a nuclear hormone receptor, programs Th17 cell development and function. With the ultimate goal of modulating inflammatory T cells in disease settings, we undertook chemical and genetic screening to identify RORγt target genes that drive human Th17 cell function. Intriguingly, our results implicated a group of genes in a novel pathway that would link lipid metabolism, RORγt activity and Th17 cell functions. We will thus test the hypothesis that Th17 cell function is controlled in large part, by RORγt target genes, via lipid droplets (LDs) (cellular organelles associated with lipid metabolism). We will take the following approaches: First, we will determine if LD- related genes – specifically, HILPDA and BNIP3 – are necessary, sufficient and specific regulators of human Th17 cell functions. Second, we will elucidate the molecular mechanisms by which LDs modulate Th17 cell differentiation. Third, using autoimmune disease models in mice, we will determine the physiological significance of LDs in inflammation and autoimmune pathologies. Our results may shed a light on novel lipid-regulatory mechanisms that control Th17 cell responses in inflammatory diseases.

摘要